-------------------------------------------------------------------------------- TITLE: Allergic Rhinitis SOURCE: Dept. of Otolaryngology, UTMB, Grand Rounds DATE: January 3, 1990 RESIDENT PHYSICIAN: Terry McMillan, M.D. FACULTY: Karen H. Calhoun, M.D. DATABASE ADMINISTRATOR: Melinda McCracken, M.S. -------------------------------------------------------------------------------- "This material was prepared by resident physicians in partial fulfillment of educational requirements established for the Postgraduate Training Program of the UTMB Department of Otolaryngology/Head and Neck Surgery and was not intended for clinical use in its present form. It was prepared for the purpose of stimulating group discussion in a conference setting. No warranties, either express or implied, are made with respect to its accuracy, completeness, or timeliness. The material does not necessarily reflect the current or past opinions of members of the UTMB faculty and should not be used for purposes of diagnosis or treatment without consulting appropriate literature sources and informed professional opinion." I. Immunology of Allergic Rhinitis A. Allergic rhinitis, atopy, or inhalant allergy are classified as Gell and Coombs type I immediate hyper- sensitivity, which is IgE mediated. 1. initial exposure produces memory cells capable of producing specific IgE 2. IgE binds to receptor sites on tissue mast cells in the mucous membranes, skin, and alimentary tract 3. in subsequent exposures to antigen, adjacent IgE molecules may be cross-linked by binding of the specific antigen 4. through a complex series of events including influx of calcium into the cell and activation of the cyclic AMP system, the mast cell degranulates 5. mediators such as histamine, SRSA, and eosinophil chemotactic factor are released by the cell 6. the most important of these is histamine, which acts to vasodilate vasculature, increase capillary permea- bility, and contract smooth musculature B. There are four classes of inhalant allergens, which are organic proteins 2-60 microns in size. 1. pollens a. characterized by seasonal swings 1.trees in spring 2.grasses in summer 3.weeds in fall b. pollen counts are at their peak in the early morning cool; onset of symptoms may occur on leaving the house in the morning c. pollen counts are attenuated by central air conditioning units 2. molds a. Alternaria is ubiquitous and considered the most prominent of molds causing allergic rhinitis b. flourish in humid climates and at low altitude c. however, molds may grow in arid climates wherever moisture collects d. symptoms are usually perennial 3. housedust a. made up of at least 28 known or suspected allergens most important of which is the dust mite b. before the advent of central air conditioning in almost all public buildings and many homes, symptoms were confined to the winter months; today symptoms are usually perennial 4. epidermals a. among the most virulent of antigens b. includes the hair and dander of domesticated animals (dogs, cats, horses, cattle) C. The basic defect in allergy is probably cell mediated. 1. IgE levels are usually elevated, but overproduction of IgE is probably only a symptom 2. a defect in T-cell suppression probably is responsible for the overproduction of IgE II. Symptoms and Signs A. Symptoms usually occur immediately or shortly after antigen exposure. B. Symptoms include sneezing, profuse clear rhinorrhea, nasal congestion, watering of the eyes, and itching of the nose and eyes. C. Symptoms wax and wane in measure to antigen exposure. D. With chronic allergen exposure, the hallmarks of nasal allergy will be seen. 1. the allergic salute represents an attemppt to alleviate itching about the nose and midface 2. the nasal crease results from thickening and scarring in the supratip area as a result of repeated "salutes" 3. facial grimacing is common as the patient twists the mouth and nose from side to side to relieve the irritation 4. chronic mouth breathing from nasal congestion may result in gingival hypertrophy and poor dental hygiene 5. the nasal mucosa is commonly found to be pale, boggy and edematous 6. allergic shiners result from venous stasis due to the chronically edematous upper respiratory tract and conjunctiva 7. Dennie's lines are horizontal grooves below the lower lashes which result from spasm of the lower lid musculature E. Complications of chronic allergic rhinitis may include sinusitis and nasal polyps. III. Diagnostic Modalities A. Skin endpoint titration (SET). 1. Compared to traditional single dilution techniques, the advantages of SET are both qualitative and quantitative. a. qualitative advantages 1. as opposed to the old scratch and prick techniques, SET offers safety, readability, and standardization a. tests are begun at dilute doses very unlikely to give severe adverse reactions b. standardized dosed are administered via standard techniques c. positive responses are well defined and are usually not equivocal 2. SET is highly sensitive. 3. A very range of allergens is available for testing and antigen vials can be prepared from almost any agent that may be suspected from the patient's history. b. quantitative advantages 1. SET allows for therapy institution at higher initial antigen doses. a. this permits more rapid achievement of the maximally tolerated dose or symptom relieving dose b. therefore, fewer injections, fewer office visits, greater convenience for the patient, and reduced expense compared to conventional technique 2. The potency of each allergen included in a multi- antigen vial can be varied independently according to the degree of sensitivity exhibited a. dosages for each allergen can then be advanced equally b. in single dilution testing as practiced by the classic allergist, all positive responding allergens are started at the same dosage 1.the final dose is limited by the most reactive antigen 2.this may result in clinically important but less reactive antigens failing to achieve the necessary dilution strength required to relieve symptoms 2. SET also allows for reassessment of quantitative sensitivity during peak season or anytime symptom relief is inadequate so that antigen doses may be appropriately adjusted. 3. The advantages of SET over single dilution techniques has been well documented in a coseasonal mountain cedar study by Lee, Knicker, and Campos which appeared in the Archives in 1982. a. 20 patients were randomly placed in each of three treatment groups 1.one group underwent SET testing and were started at the indicated antigen dosages 2.a traditional single dilution group was started at a relatively brave 1:62,500 w/v dilution 3.20 patients were treated with placebo b. injections were administered twice per week over a period of 6 weeks c. over the period of treatment, the SET patients received 11 times more antigen than the patients in the traditional group d. the SET patients had substantially more blunting of total and specific IgE at the end of treatment as compared the patients in the traditional group 4. The disadvantages of SET are overshadowed by the advantages. a. it is not tolerated well by some children b. cannot be used in patients with severe dermatologic conditions c. false positive responses are not uncommon d. there is no clinically significant correlation between the degree of sensitivity exhibited and the severity of the patient's symptoms e. does not indicate the final antigenic dose required for therapeutic relief of symptoms f. skin responses do not decrease consistently with clinical improvement 5. Antigen selection can be very difficult but is obviously very important. a. obtain information from appropriate sources about the significant aeroallergens in your area 1.allergy supply companies compile regional lists of significant pollens and molds a.compare lists from different sources; antigens that appear on all or several lists are undoubtedly significant in your region b.investigate the means used by these companies to compile their data; on-the-spot pollen counts and field surveys are the only definitive techniques for obtaining this data 2. consult with allergists in your area; those who have been practicing for some time will surely have selected out most of the important aeroallergens in your area b. A basic testing board should include representatives from all four groups of aeroallergens. 1. two or three each of appropriate tree, grass, and weed pollens should be included 2. two or three appropriate molds to include Alternaria 3. include epidermals that are suspicious from the patient's history 4. house dust should always be included c. The patient's history may be informative or misleading. 1. seasonal symptoms usually implicate a pollen 2. epidermal allergy will often be clearly identified by the patient; however, in the case of a farmer or rancher who is constantly exposed to the offending allergen, the patient may not suspect 3. resist the temptation to accept a patient's convic- tion that a particular highly visible flowering plant is the cause of his symptoms; in order for a plant to be allergenic it must: a.be a seed bearing plant; only these produce pollen b.the pollen must be produced in large quantities c.the pollen must be small enough to be windborne over large areas d.the plant must be extremely common and located near areas of human habitation 6. Preparation of antigen dilutions. a. diluents 1. normal saline usually used for testing dilutions 2. albumin saline extends saline stability by preventing adsorption of antigen to the glass vial but is expensive 3. glycerol saline is usually the solvent for antigen supplied by the manufacturer; it stabilizes the antigen but stings with injection and may interfere with the whealing response in dilution #1 b. a series of 1:5 dilutions is prepared from the supplier's stock antigen solutions 1. stock antigens are usually supplied in a 1:20 w/v dilution 2. to 1 cc of stock solution is added 4 cc of diluent to form dilution #1, which is 1:100 w/v 3. to 1 cc of dilution #1 is added 4 cc of diluent to form dilution #2, which is 1:500 w/v, and so on 4. normally, dilutions up to #6 (1:312,500) are sufficient for the testing board c. unrefrigerated boards are good for 6 weeks, refrig- erated ones for up to 3 months 7. Serial testing should be performed by a trained tech- nition or nurse using assiduous technique. a. methods 1. use disposable 26 gauge, 3/8 inch, beveled needles 2. inject intracutaneously with the bevel down to raise a 4mm wheal with .01 cc of antigen solution 3. it is safe to begin with a #4 dilution except when a pollen is in season, in which case a #6 dilution should be used 4. the first dilutions for each antigen are place in a vertical line on the upper arm; the next stronger dilutions for each antigen are then placed to the right of the previous dilution wheal to form a horizontal line 5. the results are read after 10 minutes and carefully recorded before the next stronger dilution is placed 6. controls are always placed a.the positive control is histamine phosphate b.the negative control most commonly used is a #2 dilution without the antigen included; this con- trols for glycerin and saline or albumin in the diluents b. interpreting the results 1. the endpoint is the first dilution that produces a wheal that is 2 mm larger than the prior dilution wheal and that also initiates progressively larger positive wheals 2. only the wheal diameter is significant; erythema has no clinical significance c. variations in the whealing response 1. the flash response is a huge whealing response of a very positive nature to a dilution that is weaker than the true endpoint a.it is not reproducible b.usually due to outdated antigen c.test should be repeated in 24 hours d.should not lead you to begin immunotherapy at a dilution that is too weak 2. the plateau response 3. the hourglass response B. The radioallergosorbent test (RAST) 1. test principles a. allergen is chemically linked to a solid phase support b. this allergen is incubated with a sample of patient serum c. IgE antibodies specific for the allergen will bind to it d. the solid phase is then washed to remove all unbound protein e. the solid phase is then incubated with anti-IgE anti- bodies which are radiolabeled f. unbound anti-IgE is then washed away g. bound radiolabelled anti-IgE is then quantified by a scintillation counter 2. rast in clinical diagnosis a. rast is well established as a reliable technique for determining specific IgE levels b. elevated levels of specific IgE antibodies correlate well with clinical symptoms c. RAST is less sensitive than SET but is more specific 3. advantages over SET a. very convenient for the patient; only a single blood sample is required b. no risk of adverse reaction to injected antigens c. results are not affected by antihistamines or other medications d. useful in apprehensive patients and children e. can be used in patients with dermatologic conditions 4. inappropriate uses of RAST a. as a screening test without examination by a physician b. in patients in whom nonspecific therapy is adequate c. in patients with total IgE levels below 10 U/ml d. in patients who have had negative skin testing properly performed IV. Treatment A. Theoretically, avoidance should provide the best relief of symptoms of all therapeutic modalities. 1. practically, total avoidance is nearly impossible for most aeroallergens except epidermals 2. avoidance will often require lifestyle changes that the patient is unwilling to make 3. the patient with an epidermal allergy to a family will get rid of his Otolaryngologist before he will get rid of his pet 4. avoidance will require different procedures for differ- ent allergens 5. despite the difficulties, avoidance should be a part of any therapeutic regimen to the extent that the patient is willing to practice it B. Antihistamines are competitive inhibitors of histamine at the histamine receptor site 1. there are several classes of antihistamines which very in their potency and the degree of the major side effect, sedation 2. are beneficial in controlling sneezing, rhinorrhea, and itching; not very good for congestion 3. if an antihistamine from one class is not effective, a drug from another class may be 4. terfinidine (Seldane) crosses the blood-brain barrier poorly and so produces little sedation 5. astemizole (Hismanal) requires only once per day dosage and is best used in a prophylactic manner; there is evidence that effects of Hismanal may last for up to 2 weeks after discontinuation of use 6. antihistamines are of little use in vasomotor rhinitis or viral rhinitis C. Sympathomimetics are used in combination with antihista- mines to aid in relief of nasal congestion 1. may stimulate alpha or beta receptors or both 2. side effects may include elevation of blood pressure or cardiac stimulation 3. should not be used in patients with hypertension or heart disease D. Topical nasal decongestants must be used cautiously. 1. may be used beneficially in extreme cases 2. should be discontinued after several days use 3. abuse results in rhinitis medicamentosa 4. combinations of topical decongestant with steroid, antibiotics, or other medications are to be avoided; damage to the ciliary system may occur E. Chromolyn sodium is recently becoming very popular for use in allergic rhinitis. 1. inhibits mast cell degranulation by inhibiting calcium influx into the cell 2. very few complications or side effects have been described 3. does not alleviate acute symptoms; must be used prophy- lactically 4. should be used religiously throughout the pollen season or year round for perennial allergy F. Steroids can have potent effects in relieving symptoms of allergic rhinitis. 1. systemic steroids a. mechanisms of action 1. do not inhibit or prevent the allergic event itself but rather diminish the tissue responses 2. decrease capillary permeability, inhibit leukocyte migration, and reduce formation of prostaglandins, thromboxanes, and leukotrienes b. major side effects 1. adrenal suppression 2. promotion of gastric ulceration 3. osteroporosis 4. subcapsular cataract formation 5. immune suppression c. indications 1. for severe acute pollenosis 2. severe exacerbations of seasonal allergic symptoms 3. in severe rhinitis medicamentosa, at the time of topical decongestant withdrawal 4. short acting forms such as prednisone should be used for no more than seven to ten days 5. systemic steroids should be respected, not feared 2. topical nasal steroids a. dexamethasone was the first agent to be used in this manner but has fallen into disfavor because of signif- icant systemic absorption and possible side effects b. beclomethasone has very little systemic absorption and may be used safely in pregnancy c. nasalide demonstrates some systemic absorption, so exceeding recommended dosages should be discouraged d. local side effects include stinging, irritation, crusting, and rarely septal perforation e. in order for the agent to be effective, it must reach the nasal mucosa; at initiation of treatment should be combined with antihistamine/decongestant combinations or topical nasal decongestant 3. intranasal steroid injection a. major advantage is rapid onset (1-2 hours) and prolonged duration of effect (3-6 weeks) b. very effective for relief of severe flares of allergic rhinitis c. systemic effect not clinically significant if use is not abused d. frees the patient from daily use of other agents e. most common side effect is ipsilateral facial flushing which occurs one day after injection and requires no therapy f. several cases of ipsilateral blindness both temporary and permanent due to retinal vasospasm or embolization have been described g. this horrible complication can be avoided by use of proper technique 1. inject only at the anterior end of inferior turbin- ates after careful cocainization of the injection sites 2. never mix a local anaesthetic or epinephrine with the steroid 3. draw material up fresh for each injection to avoid clumping 4. inject material very slowly; if resistance is encountered, try another site--do not force 5. injection in the proper plane produces blanching h. suitable repository steroids for this use include triamcinolone acetonide (kenalog 40) and triamcina- lone acetate (Aristacort Forte) i. should not be performed more than four times per year j. if four injections do not give adequate relief, the patient's immunotherapy regimen should be reviewed k. do not inject before symptoms begin or repeat before symptoms recur G. Immunotherapy requires considerable expertise, added expense and personnel. 1. immunologic changes seen with successful treatment a. results are specific; patients experience relief only for the treated antigens b. administration of high doses os allergen is required to produce clinical improvement c. skin reactivity to treated antigens is usually reduced d. specific IgE levels are decreased e. the concentration of specific IgG blocking antibodies rises dramatically; binding of antigen by the blocking antibody rather than IgE is the primary mechanism of effect 2. indications a. inadequate response to avoidance and pharmacotherapy b. almost always indicated in severe aeroallergen sensi- tivity c. when the severity of the symptoms outweighs the hassles and cost of immunotherapy d. when the patient is likely to comply with the rigid schedule of injections for 2 to 3 years 3. SET based therapy a. therapy for each antigen is begun at a strength five times the endpoint dilution b. each succeeding dose is increased by five times the endpoint dilution c. several antigens are mixed in the same treatment vial d. injections are given once or twice per week until the maximally tolerated dose is reached; then the frequency of injections is decreased to the minimum required to maintain therapeutic effect e. the maximally tolerated dose has been reached when: 1. an erythematous, hot injection site occurs 2. clinical symptoms occur shortly after injection 3. a systemic reaction occurs after injection f. two to three years of therapy are usually adequate to maintain tolerance; if recurrence occurs after discontinuation of therapy, another course should be instituted 4. RAST based immunotherapy a. immunotherapy can be instituted with confidence based on RAST scores alone; a well documented schedule has been established which can be used b. it is mandatory that a small dose skin test challenge be place before institution of therapy c. the recommended schedule allows delivery of higher doses of antigen earlier than with SET based therapy d. higher levels of blocking IgG antibody are produced earlier in RAST based compared to SET based therapy 5. Potential causes of immunotherapy failure a. an incorrect diagnosis was made (wrong antigen treated) b. inadequate environmental control measures c. maintenance doses not high enough d. maintenance doses too high e. concommitant food or chemical sensitivity f. underlying medical problems not addressed such as nasal polyps or chronic sinusitis g. patient uses medications that cause nasal congestion such as reserpine, oral contraceptives ------------------------------------------------------------------- BIBLIOGRAPHY 1. Lee LK, Kniker WT, and Campos T: Aggressive coseasonal immunotherapy in mountain cedar allergy. Arch Otolaryngol 108:787,1982. 2. Trevino, RJ: IgG levels after treatment with antigen based on the scratch testing, intradermal testing, modi- fied RAST testing. Otolaryngol Head Neck Surg; 95: 307, 1986. 3. Mabry RL: Corticosteroids in Otolargngology:intraturbinal injection. Otolaryngol Head Neck Surgery;91:217,1983. 4. Mabry RL: Chromolyn sodium aerosol. Otolaryngol Head Neck Surgery; 93:135,1985. 5. Nalebuff DJ, Fadal RG, Ali M.: Determination of initial dose for ragweed hypersensitivity with modified RAST. Otolaryngol Head Neck Surg; 89:271,1981. 6. Krause, Helen: Otolaryngologic Allergy and Immunology; WB Saunders, 1989. 7. Becker, Gary: Introduction to Otolaryngic Allergy; published by AAO-HNS, 1986. 8. Goldman, Joseph: Principles and Practice of Rhinology; chapters 13,14,15; John Wiley and Sons, 1987. 9. King, Hueston: Endpoint titration and immunotherapy. Otolaryngologic Clinics of North America; 18:4;nov. 1985. 10. Wasserman SI: Mediators of immediate hypersensitivity. J Allergy Clin Immunol; 72:101,1983. ------------------------------END-----------------------------------------------